Protected active compound formulations of amino acids and process for their preparation

ABSTRACT

Active compound formulations for animal nutrition of amino acids, vitamins, enzymes and pigments, which are suitable for providing the active compounds in protected form for the nutrition of stock animals, in particular ruminants, and a process for the preparation of these protected active compound formulations.

REFERENCE TO RELATED APPLICATION

This application claims the benefit of provisional patent application60/379,403 filed May 13, 2002 which is relied on and incorporated hereinby reference.

INTRODUCTION AND BACKGROUND

The present invention relates to protected active compound formulationsof amino acids, in particular methionine, and of vitamins, pigments orenzymes and a process for the preparation of these protected activecompound formulations. This invention relates in particular to activecompound formulations of amino acids which are suitable for providingamino acids in a rumen-protected form for the nutrition of stockanimals, in particular ruminants. In a further aspect, the presentinvention relates to feedstuff containing the protected active compoundformulations and method of using same.

Methionine or its substitute, the methionine hydroxy analogue, have beenemployed very successfully for decades in animal nutrition as additivesfor meeting the requirement of stock animals for the essential aminoacid in a economical but also in a physiologically and ecologicallyoptimum manner. However, methionine or also the hydroxy analogues cannotbe employed directly in the nutrition of ruminants, since the microbesliving in the rumen metabolize amino acids, hydroxy acids and proteinsrelatively rapidly. If unprotected amino acids or hydroxy acids are fedto ruminants, the predominant proportion of these amino acids or hydroxyacids would therefore not be available to the ruminant for its ownsupply, but would be lost for protein synthesis in metabolism bymicrobial breakdown in the rumen.

A large number of so-called rumen-protected products are known in theprior art, but a predominant number thereof are not stable enough tomicrobial breakdown in the rumen to ensure an appropriate use as anadditive. The best products to date are based on the use of relativelylarge shaped pieces of methionine, such as, for example, granules orpellets, which are protected by coating with polymers. Ethylcellulose(EP 0 495 349) or a copolymer of vinylpyridine and styrene (U.S. Pat.No. 4,877,621 and U.S. Pat. No. 4,876,097) is used, for example, as thecoating composition.

The products described in EP 0 495 349 comprise a shaped piece ofmethionine which is obtained by pelleting methionine and auxiliarysubstances and is then coated with a protective shell of ethylcellulose,preferably in 2-layer application with an inorganic auxiliary substanceor filler (e.g. sodium aluminum silicate). The cylindrical shape of thepellets resulting from the preparation leads to edges with a relativelythin coating, which are regarded as intentional breaking points and asessential for the release of the active compound.

EP 0 495 349 (comparison example 5) furthermore reports that rounded-offparticles with a uniformly thick film thickness show adverse effects.

The products obtained in EP 0495 349 release methionine in the entiredigestive tract, relatively little in the rumen, which can be seen fromthe high in vitro rumen protection of ≧80%, but increasingly more in thefurther digestive tract of the abomasum and small intestine. Thesedelayed release properties, also called “slow release” properties, arepreferred here since a small introduction of methionine in the rumenstabilizes the rumen flora. This is favorable overall, and a slowuniform release of methionine in the further course of digestion leadsto a more uniform utilization than a sudden pH-controlled release in theabomasum at pH 2, which is aimed for with the products from U.S. Pat.No. 4,877,621 and U.S. Pat. No. 4,876,097.

On the basis of the size of the particles shown in EP 0 495 349 ofapprox. 3.5 mm length, however, stable homogeneous distribution of suchproducts in feed mixtures is not always easy to achieve, on the one handbecause of the small number of particles, due to the size, per volumeand on the other hand because of the difference in size with respect tothe other mixed feed components, which can lead to demixing in somecases under adverse conditions. On the other hand, there is nomechanical stability when exposed to very high stresses, such as e.g.during pelleting of the feed.

The protected products described in U.S. Pat. No. 4,877,621 and U.S.Pat. No. 4,876,097 are based on coating of pellets which comprise aminoacids and have diameters of 0.1 to approx. 5 mm, a pH-sensitiveprotective shell being built up. Since the intention is to producepH-dependent release properties, a copolymer of 2-vinylpyridine andstyrene is always used here as an essential constituent, and in U.S.Pat. No. 4,876,097 additionally further components, such as e.g. zeincellulose acetobutyrate, polyvinyl acetate, chitosan, ethylcellulose andfurther auxiliary substances, including various solvents, which leads toa complicated protective shell comprising several components. Therelease properties indeed show entirely good results, but are achievedat the expense of a high complexity and by the use of coating orauxiliary substances which in some cases have not yet been approved infeedstuffs legislation, which makes economical utilization difficult.

EP 0 614 615 relates to a feedstuffs additive of a rumen-protectedcomposition which comprises a biologically active substance and aprotective shell and furthermore also has a pelleting-resistantprotective shell of natural or synthetic polymers. Polymers which aresuitable for this pelleting-resistant protective shell have anelasticity modulus at 30° C. of between 10⁸ and 10¹¹ dynes/cm² and aglass transition temperature of between 50° C. and 150° C. Thiscomposition comprises pelleted granules with a particle size of greaterthan 1.5 mm.

U.S. Pat. No. 5,290,560 describes a process for the preparation ofgranules by extrusion with food or medicament active compounds forruminants, in which the core of the granules is extruded in a first stepand the core is coated by pulverization in a second step.

EP 588 346 describes a process for the preparation of 1.5 mm granules byextrusion with food or medicament active compounds for ruminants, inwhich the core of the granules is extruded in a first step and the coreis coated by fluidized bed coating in a second step. The feedstuffsadditive composition for ruminants described here comprises a coatedcore of the biologically active substance. The biologically activesubstance is an amino acid, such as e.g. lysine or methionine. Thecoating material comprises hydrogenated animal fat, oil or wax and analiphatic monocarboxylic acid and/or nucleic acid, nucleotides,nucleosides, bases containing nucleic acid or salts.

In view of the problems described, it was an object to provide an activecompound formulation which does not have the above-mentioneddisadvantages of the existing products or has them to a significantlysmaller extent and shows the advantages of the “slow release” propertiesdescribed in EP 495349, that is to say an increased release after >6 h(≅residence time in the rumen).

One possibility of achieving the object described chiefly comprisescoating of significantly smaller particles. However, this possibility onthe one hand has the disadvantage of increased consumption of oftenrelatively expensive coating compositions. On the other hand,multi-layer application with additional components (fillers), whichallow later dissolution of the protective shell at the desired place,such as is necessary in the case of the products described in EP 0 495349, can scarcely be realized with very small particles (see EP 0 614615, comparison examples 1-6).

SUMMARY OF THE INVENTION

An object of this invention is therefore to provide a protected activecompound formulation which is based on amino acids, in particularmethionine or salts thereof, and has a particle diameter of less than1000 μm. Furthermore, a rumen-protected active compound formulationshould be coated with a protective shell and by one-layer application,so that analogous rumen protection rates compared with the products e.g.from EP 0 495 349 and distribution properties in the mixed feed whichare moreover improved are obtained.

This rumen-protected active compound formulation based on amino acidsshould meet the requirement of being able to be absorbed to an increasedextent under the conditions of the subsequent abomasum or at the latestin the small intestine of the ruminant. Active compounds which areemployed are, for example, amino acids or salts thereof, vitamins,pigments or enzymes.

In addition, the formulation should have the highest possible mechanicalresistance, so that no relatively large losses of intactly protectedparticles occur during the typical processes of preparation of mixedfeeds, such as mixing, conveying or pelleting.

This requirement profile should furthermore as far as possible beachieved only with the aid of auxiliary substances which are approved infeedstuffs legislation and in the end move the active compoundformulation into a price frame which does not exceed that of the currentproducts on the market. These requirements are summarized in thefollowing:

In vitro release after 6 hours:

corresponds to the protection rate in the rumen, i.e. a maximum of 25%release/digestion of the biologically active substance in the rumen at apH of 5.5-6.5, in approx. 6 hours (h) and in the presence of microbes,protozoa;

In vitro release after 6-24 hours:

corresponds to release in the further digestive tract after a residencetime of more than 6 h to 24 h and should be 35-65% of the biologicallyactive substance initially contained in the product,

The active compounds and coating materials should withstand theconditions of feed processing of mixing, conveying and pelleting(approx. 80° C.-100° C., steam, pressure, shear forces).

The product according to the invention meets these conditions.

It has furthermore been found that the “slow-release” active compoundformulations according to the invention are also resistant to theoxidation action of air, the effects of water or of trace elements, e.g.during storage in bulk or in a feed mixture. The active compoundformulations according to the invention can moreover be employed inother uses in which a controlled “slow-release” type of release isdesirable, such as e.g. in the case of vitamins, pigments or enzymes.

A further object of this invention is to provide a process for thepreparation of these protected active compound formulations.

This object is achieved in respect of the active compound formulation inthat the desired active compound, in particular methionine, is employeddirectly in the form of particles or crystals with a diameter of lessthan 1 mm (1000 μm) without a prior granulation step, or spray granuleswith a diameter of less than 1 mm. The particle diameter is that beforethe coating. The shape of the particles to be processed is notparticularly critical, it is therefore possible to employ bothcommercially available platelet-shaped crystals and circular crystals.It has been found that, for example, methionine particle coatedaccording to the invention with a diameter of less than 1 mm haveanalogous rumen protection rates compared with the products described inEP 0 495 349 (comparison example 5).

DETAILED DESCRIPTION OF THE INVENTION

The active compound formulations according to the invention in generalcomprise small coated active compound particles in the particle sizerange of 100 to 1000 μm, in particular 200 to less than 800 μm,preferably 300 to 700 μm, particularly preferably 400 to 600 μm.

The active compound formulation according to the invention are coatedwith at least one protective shell. The protective shell can comprise asingle coating material or a composition of coating materials.Protective shells of a single coating material are preferred in thisinvention. Active compound formulations with a single protective shellproduced by one-layer application are particularly preferred.

Coatings based on film-forming agents comprising naturally occurring ormodified naturally occurring polymers or homo- and copolymers which canbe prepared by conventional known processes are suitable for theprotective shell. Synthetic polymers are also suitable. Such suitablepolymers are, for example, cellulose esters, ethers, acrylates,poly(meth)acrylates, polyamides, polyesters or copolymers of e.g.acrylonitrile, styrene, ethylene, propylene, butadiene, or esters andamides of methacrylic acid or acrylic acid.

A coating based on cellulose ethers, preferably ethylcellulose, is veryparticularly suitable. It is particularly preferable to useethylcellulose dissolved in ethanol, since a coating with a content of 4to 30 percent by weight (wt. %), preferably 5-20 wt. % and particularlypreferably 9-15 wt. % ethylcellulose, based on the end product, can beachieved in this manner.

Various ethylcellulose types can be employed as the coating compositionaccording to the invention. Thus, it has been possible to employethylcellulose types of varying viscosity according to the differentdegree of substitution all from Hercules (N10, N50, T50, X200) by way ofexample, and to achieve similarly advantageous results here. Theethylcellulose types investigated here by way of example correspond tovarious viscosity classes. The number corresponds to the dynamicviscosity in mPa*s measured in a 5% solution in toluene/ethanol 80:20(w/w) at 25° C.

The active compound formulations according to the invention can beproduced in an advantageous manner by fluidized bed coating, butoptionally also by other processes of microencapsulation, such as forexample, coacervation.

It has been possible here, in an unforeseeable manner, to dispense withthe use of further inorganic or organic auxiliary substances, such ase.g. sodium aluminum silicate or the Na salt of carboxymethylcelluloseor other substances described in the above-mentioned patents, whichleads to a significant simplification of the process and of the activecompound formulations and to the direct utilizability of such activecompound formulations without prior, tedious feedstuffs legislationapproval processes.

It has been found that methionine crystals in particular can be employeddirectly without a prior granulation step. It is possible here to employboth platelet-shaped crystals and round crystals of conventionalcommercial quality.

The preferred particle size of the active compound formulation of400-600 μm for the subsequent coating can be achieved by simpleoperations such as sieving, air sifting or another separation processfrom the prior art, it as a rule being sufficient to carry out a singleseparation operation, such as for example, a sieving over a 400 μmsieve, because the commercially available methionine products scarcelyhave contents above 600 μm.

To produce round crystals, if this is desired, methionine particles withthe conventional platelet shape can optionally also be rounded off orgranulated, with or without the presence of further auxiliarysubstances. The consumption of coating composition is lowest in the caseof round particles.

It is also possible to employ spray granules prepared from methioninesolutions or methionine salt solutions, such as e.g. Na, K, Ca, Mg, Znmethionate in pure or mixed form, which have a rounded-off shape due tothe preparation.

To prepare the active compound formulations according to the inventionby fluidized bed coating, DL-methionine, for example, in the particlesize range of significantly smaller than 1000 μm is initially introducedinto a fluidized bed apparatus and sprayed with a coatingcomposition—preferably ethylcellulose—dissolved in an organic solvent.The conditions are adjusted such that a covering of the particles whichis as complete as possible is achieved with minimal agglomeration.

The preparation of the active compound formulations according to theinvention and the test methods used for their characterization aredescribed in the following.

EXAMPLES 1-9 AND COMPARISON EXAMPLES A AND B

Determination of the Release Properties

Rumen protection rate [%]=Content of the still protected methionineafter an incubation time of 6 to 24 h in a test medium (water pH 5.5 orbuffer solution).

Release Test (In Vitro) For Active Compound Formulations WithpH-Independent Release Properties

The active compound formulation is shaken in desalinated water at 37°C./pH 5.5 in a vibrating water-bath—desired value typical for product A(protected methionine, pellet-shaped approx. 1.8*3.5 mm, analogously toex. 11 from EP 0 495 349)

for 6 h (≅rumen) high >80%

for 24 h (≅rumen and further digestive tract) low approx. ≦45%

After the particular period of time in the vibrating water-bath, thesolutions were filtered, the methionine released from the protectedactive compound formulations was determined quantitatively in thefiltrate ( by bromide/bromate titration) and the protection rate wascalculated according to the following formula:

Protection rate [%]=1- % methionine released/% methionine startingamount)*100 The use, preferred here, of desalinated water instead of thebuffer mixtures described in EP 0 495 349 leads to equivalent results ininvestigations on pH-independent “slow release” systems (comparisonexample B).

The in vitro protection rates after incubation for 6 h measured in thismanner have a tendency to correlate well according to EP 0 495 349 withresults of in vivo experiments. On the other hand, the in vitroprotection rates after incubation for 24 h are not identical to theprotection rates or corresponding release rates to be determined inliving systems. As EP 0 495 349 shows, in vitro protection rates of30-40% after 24 h (corresponds to release of approx. 45-55%) correspondto good in vivo bioavailabilities (=methionine content in blood plasma),so that the 24 h laboratory value is to be seen here as a guidelineparameter.

Determination of the Stabilities Towards Pelleting

Preparation of the Mixtures

Milk yield feed ML 183 (Raiffeisen, Wiesbaden) was mixed together withthe corresponding amounts of protected methionine active compoundformulation according to the invention in a 50 L Lödige mixer for 4 minat 100 rpm. The finished mixtures were employed for pelleting.

The preparation of feed pellets was carried out in a Walther EI 15 pressunder the pelleting conditions stated in table I. This was first startedup with feed containing no active compound. After a constant press runhad been reached, the mixtures were pressed successively with varioustest products.

The pellets were cooled slowly, the fine content (particle size <3 mm)was sieved off and the finished batches were unloaded. TABLE I PELLETINGCONDITIONS Press Walther EI 15 Die bore 5.5 mm Channel length 30 mmCurrent uptake 6.3-6.8 A Pelleting temperature 65-75° C. Steam pressure8 bar Concentration of test substance 3% DL-methionine weight equivalentin milk yield feed Pellet size 5.5 * 10-12 mm Residual moisture contentafter cooling approx. 11%

The protection rates were measured on the feed pellets prepared in thisway in a vibrating water-bath as described above. The methioninereleased was quantified here by HPLC chromatography.

Preparation of the Protected Methionine Particles

The experiments were carried out in a laboratory fluidized bedgranulating unit. In each case 1 kg of sieved methionine (particle rangeas stated in table II) per experiment was initially introduced into thefluidized bed apparatus as the starting material. Either platelet-shapedcrystals (Degussa AG) or crystals with a round particle shape (Sumitomo)were used. Various ethylcellulose types from Hercules Aqualon (viscosityclass N10, N50, T50, X200 as stated in table II) were employed for thecoating. Ethylcellulose was sprayed as a 5% ethanolic solution through anozzle from the top on to the methionine particles held underneath inthe fluidized bed.

Comparison examples A and B were coated in accordance with EP 0 495 349with 2 layers of different coating materials.

Nitrogen was employed as the drying and atomizing gas and the unit waskept in the non-explosive range in this manner. The following testsettings were used:

Intake temperature: 110° C.

Bed temperature: 85-90° C.

Waste air temperature: 77-80° C.

Inflow volume flow: 90 mN³/h

Atomization pressure: 3 bar

The consumption of coating composition was monitored continuously andintermediate samples were taken from the fluidized bed apparatus atregular intervals of time. Both on the intermediate samples and on theend sample, the methionine content was determined and a release test wascarried out to determine the protection rates.

In this manner it was possible to determine the protection rates as afunction of the methionine content and of the complementary content ofcoating material for each combination of methionine and coatingmaterial. All the results in this respect are listed in table II.

By pelleting the active compound formulations according to the inventionin milk yield feed and subsequent repetition of the release test, theprotection rate after pelleting was additionally determined as a measureof the stability towards pelleting (table II). TABLE II Methionineactive compound formulations protected by coating Example/ Protectionrates (in vitro) comparison Rumen After example Coating materialMethionine after 6 h, Total after Release 6 h: pelleting 6 h, no.Methionine quality Content, %, type content % % 24 h, % 24 h, % % 1platelets  8.3, EC N10 91.7 22 5 17 nm¹ 400-600 μm 16.6, EC N10 83.4 7340 33 2 platelets  4.7, EC N50 95.3 6 3 3 nm¹ 400-600 μm 12.0, EC N5088.0 63 22 41 3 platelets 19.9, EC N50 80.1 80 53 27 30 400-600 μm 4round crystals  4.3, EC N50 95.7 49 18 31 400-600 μm  6.8, EC N50 93.269 39 30  8.7, EC N50 91.3 79 52 27 11.2, EC N50 88.8 83 60 23 13.2, ECN50 86.8 89 71 18 26 A platelets  5.6, EC N50 90.7 26 6 20 nm¹ 400-600μm  2.2, Wessalith P 5 platelets  7.5, EC T50 92.5 35 nm¹ nm¹ 400-600 μm10.4, EC T50 89.6 54 15 39 14.2, EC T50 85.8 71 32 39 17.6, EC T50 82.481 46 35 20.9, EC T50 79.1 86 56 30 34 6 platelets  6.6, EC X200 93.4 26nm¹ nm¹ 400-600 μm  8.9, EC X200 91.1 42 10 32 14.4, EC X200 85.6 66 3234 17.8, EC X200 82.2 75 49 26 18.5, EC X200 81.5 77 46 31 34 7 roundcrystals  6.0, EC N50 94.0 13 nm¹ nm¹ 100-300 μm 12.9, EC N50 87.1 57 1740 15.6, EC N50 84.4 66 27 39 15.8, EC N50 84.2 63 30 33 8 8 roundcrystals  4.9, EC T50 95.1 14 nm¹ nm¹ 100-300 μm 10.2, EC T50 89.8 55 2134 15.1, EC T50 84.9 74 42 32 8 9 platelets  7.9, EC N50 92.1 27 nm¹ nm¹100-300 μm 14.5, EC N50 86.5 23 nm¹ nm¹ 16.9, EC N50 84.1 37 nm¹ nm¹19.2, EC N50 80.8 41 7 34 21.6, EC N50 78.4 37 9 28 nm¹ B Pelletsanalogously  4.6, EC N50 84.8 82 42 40 15 to ex. 11 from EP  2.3, Na Al0495349 silicate 1800-3500 μm¹nm = not measured

As can easily be seen from table II, when sieved platelet-shapedmethionine with a particle size of 400-600 μm is employed at anethylcellulose application of approx. 17%, protection rates of 81% after6 h and 46% after 24 h are found in the standard test (see ex. 5). Withround DL-methionine crystals, rumen protection rates of 79% after 6 hand 52% after 24 h were already found with an ethylcellulose applicationof 8.7% (see ex. 4).

In both cases, the protection rates were in the range of the valuesmentioned in EP 0 495 349. In the case of the rounded-off crystals,approximately the same protection rates as in the case of theplatelet-shaped crystals were achieved with about half the applicationamount.

After pelleting in milk yield feed, it was still possible to obtain invitro rumen protection rates of up to 34% after 6 h (ex. 5, 6), whichmeans a significant improvement compared with the products from EP 0 495349, which are less stable to pelleting because of their size(protection rate after pelleting (6 h): 15%, comparison example B).Protected active compound formulations with a particle size of 100 -300μm of the methionine particles employed led to protection rates afterpelleting which were again lower, which suggests that the optimum rangehas already been left again here. (Example 7 and 8, protection rateafter pelleting (6 h): 8%)

Protection rates after 6 h of at least 60%, preferably of more than 70%,in particular of more than 80%, and by comparison with thiscorrespondingly lower protection rates after 24 h, which are at least30%, preferably at least 35%, but in particular more than 40% belowthose after 6 h, have proved, according to the disclosure of EP 0 495349, to be a prerequisite for the bioavailability (increase in themethionine blood plasma level) to ruminants which is described there.

In general, the products of the invention have a protection rate in thein vitro release test after 6 hours of 60-90%, and after 6-24 hours of35-50% after 24 hours, preferably protection rates in the in vitrorelease test after 6 hours of 75-85%, and after 6-24 hours of 35-50%after 24 hours.

In principle, a higher protection rate is achieved with a higher layerapplication. However, too high a protection has the effect in turn thattoo little of the protected amino acid is available to the animal. Onthe basis of the disclosure in EP 0 495 349, it was to be assumed thatround particles do not bring about favorable release properties becauseof their uniform layer thickness. However, against expectation it hasbeen found that small round and also platelet-shaped particles with aparticle size of between 100 μm and 1000 μm which are coated with asingle covering with a single protective shell, in particular ofethylcellulose have favorable release properties equivalent to theproducts from EP 0 495 349, as shown, in particular, by the comparisonof examples 3, 4, 5, 6 with comparison example B.

In addition to the release properties and the mechanical stability, itis also important that feed mixtures show as little tendency towardsdemixing as possible during handling, that is to say the lowest possibledemixing on trickling. To obtain information on the demixing propertiesof the active compound formulations according to the invention duringtrickling compared with conventional products, these were mixed into theusual feed for ruminants and a trickling demixing test was carried out.In this, the initially homogeneously mixed feed mixtures were allowed totrickle through a discharge funnel and a poured cone was produced inthis manner under standardized conditions, samples being taken in thisat various defined points for analysis of the methionine content. Thistrickling demixing test is described in examples 10-25 and comparisonexamples C and D.

EXAMPLES 10 TO 17, COMPARISON EXAMPLES C-F

Determination of the Tendencies Towards Demixing

Mixtures of the active compound formulations according to the inventionwith the usual feedstuffs were prepared. For this, both commerciallyavailable mineral feed, such as Blattin (Höveler) and Spur-a-min(Höveler) and organic feed such as soya meal (Raiffeisen) and milk yieldfeed (Raiffeisen) were mixed with protected methionine active compoundformulations according to the invention as stated in table III and auniform mixture was produced in a tumble mixer. The particle sizedistributions of the feed types employed is stated in table IV.

The mixtures produced in this manner were investigated for theirtendencies towards demixing during trickling in the following test. Forthis, the mixtures were in each case transferred to a glass funnel andallowed to run out from a falling height of 10 cm on to a flat base. Thedimensions of the funnel were: diameter 100 mm, cone height 90 mm,diameter of the discharge 7 mm, discharge length 90 mm, falling heightfrom the discharge 100 mm.

The cone formed in each case was divided into 3 layers of equal height,the layer produced in each case was ground (<250 μm) and the methioninecontent was determined in each layer by HPLC chromatography. From the 3methionine contents of the 3 layers, the variation coefficients wasdetermined as a measure of the demixing during trickling. The higher theparticular variation coefficients found, the greater the particulardemixing during trickling. The smaller the variation coefficients, thelower the demixing of the particular product from the particular feedmixture during trickling. The results are summarized in table V.

The variation coefficient (VC) of the trickling demixing experimentswere calculated according to the following formula:VC [%]=(standard deviation of the individual measurements/mean of theindividual measurements)*100

TABLE III ACTIVE COMPOUND FORMULATIONS WITH THE USUAL FEEDSTUFFSExample/com- parison example no. Batch with 10 11 C 12 13 D Blattin, g200 200 200 Spur-a-min, g 200 200 200 End product from 25.28 25.28 ex. 5(79.1% methionine), g End product from 23.04 23.04 ex. 4 (86.8%methionine), g Product A¹ (86.6% 22.91 22.91 methionine) Methionine 8.98.9 8.9 8.9 8.9 8.9 content (calculated), % Soya extracted 200 200 200meal, g Milk yield 200 200 200 feed, g End product from 3.03 3.03 ex. 5(79.1% methionine), g End product from 2.76 2.76 ex. 4 (86.8%methionine), g Product A¹ (86.6% 2.77 2.77 methionine) Methionine 1.21.2 1.2 1.2 1.2 1.2 content (calculated), %¹Product A = protected methionine, pellet-shaped approx. 1.8 * 3.5 mm,analogously to ex. 11 from EP 0 495 349.

TABLE IV PARTICLE SIZE DISTRIBUTION AND BULK DENSITY OF THE FEEDSTUFFSEMPLOYED Milk yield Particle size Blattin Spur-a- Extracted feed MLdistribution M24 ADE min soya KFW 183 <100 μm [%] 4.4 20.8 3.2 8.4100-150 μm [%] 3.6 7.1 1.2 4.6 150-200 μm [%] 5.0 8.0 1.3 5.5 200-300 μm[%] 10.6 18.0 3.7 11.3 300-500 μm [%] 15.5 156 8.9 17.2 500-710 μm [%]14.8 9.0 9.8 11.9  710-1000 μm [%] 21.5 11.2 15.4 12.2 1000-1400 μm [%]18.5 8.2 22.6 14.6 1400-2000 μm [%] 5.6 1.7 18.7 7.3 2000-3150 μm [%]0.6 0.4 12.2 7.0 >3150 μm [%] 30 Bulk density [g/L] 1009 833 618 552

TABLE V DEMIXING OF PROTECTED METHIONINE ACTIVE COMPOUND FORMULATIONSDURING TRICKLING Example/ compari- Methionine son Protected content inthe example methionine from poured cone, VC no. Feedstuff example no.[%] [%] 10 Blattin M24 Ex. 5 top: 8.9 7 ADE (platelets) middle: 10.0bottom: 10.0 11 Ex. 4 top: 7.7 9 (round middle: 8.8 particles) bottom:9.1 C Blattin M24 product A¹ top: 12.8 60 ADE middle: 2.9 bottom: 9.9 12Spur-a-min Ex. 5 top: 8.1 28 (platelets) middle: 8.4 bottom: 13.1 13 Ex.4 top: 6.8 38 (round particles) middle: 6.5 bottom: 12.3 D Spur-a-minproduct A¹ top: 6.2 70 middle: 3.5 bottom: 14.3 14 Soya Ex. 5 top: 1.346 extracted meal KFW (platelets) middle: 1.5 bottom: 0.5 15 Ex. 4 top:0.9 38 (round particles) middle: 1.3 bottom: 0.6 E product A¹ top: 1.131 middle: 0.9 bottom: 1.7 16 Milk yield Ex. 5 top: 1.2 18 feed ML 183(platelets) middle: 1.3 bottom: 0.9 17 Ex. 4 top: 0.8 7 (roundparticles) middle: 0.8 bottom: 0.9 F product A¹ top: 0.9 27 middle: 1.1bottom: 1.5¹Product A = protected methionine, pellet-shaped approx. 1.8 * 3.5 mm,analogously to example 11 from EP 0 495 349

The greater the differences in the contents analyzed within the pouredcone, the greater the demixing has been during trickling. The variationcoefficient of the content determination therefore serves as a measureof the demixing during trickling.

The comparison of examples 10 and 11 with comparison example C orexamples 12 and 13 with comparison example D shows, in mixtures of themineral feeds Blattin and Spur-a-min with the protected active compoundformulations according to the invention, significantly lower variationcoefficients of 7-9% and 28-38% respectively compared with conventionalproducts with 60 and 70% respectively.

In the case of soya extraction meal as the carrier material, comparableVC values were still found with 38-46% in comparison with 31% (examples14 and 15 compared with comparison example E).

In milk yield feed, the VC values of the active compound formulationsaccording to the invention of 7-18% were in turn more favorable than inthe case of conventional products with 27% (examples 16 and 17 comparedwith comparison example F).

The significantly lower demixing of the active compound formulationsaccording to the invention during trickling increases the certainty thatthe animals fed are supplied more uniformly with the feed startingsubstances in question, and therefore contributes towards better feedingresults, which is of decided advantage from economic and ecologicalaspects.

Further modifications and variations of the invention will be apparentto those skilled in the art from the foregoing and are intended to beencompassed by the claims appended hereto.

German priority application 102 20 785.2 filed May 10, 2002 is relied onand incorporated herein by reference.

1. An active compound formulation protected by a coating, whichcomprises as the active compound an amino acid or salt thereof, having aparticle diameter of less than 1000 μm, and which is coated with aprotective shell, and having delayed release properties.
 2. The activecompound formulation as claimed in claim 1, wherein the active compoundis present in the form of crystals or granules.
 3. The active compoundformulation as claimed in claim 1, which is present in the form ofplatelet-shaped particles or platelet-shaped crystals, or roundcrystals.
 4. The active compound formulation as claimed in claim 2,which is present in platelet-shaped particles or platelet-shapedcrystals, or round crystals.
 5. The active compound formulation asclaimed in claim 2, wherein the active compound is methionine in theform of crystals, granules or spray granules.
 6. The active compoundformulation as claimed in claim 2, wherein the active compound is amethionine salt in the form of crystals, granules or spray granuleswhich are suitable for feedstuffs.
 7. The active compound formulation asclaimed in claim 6, wherein the methionine salt is a Na, K, Ca, Mg, orZn methioninate in pure or mixed form.
 8. The active compoundformulation as claimed in claim 1, wherein the protective shellcomprises a single coating material and is coated by one-layerapplication.
 9. The active compound formulation as claimed in claim 2,wherein the protective shell comprises a single coating material and iscoated by one-layer application.
 10. The active compound formulation asclaimed in claim 3, wherein the protective shell comprises a singlecoating material and is coated by one-layer application.
 11. The activecompound formulation as claimed in claim 4, wherein the protective shellcomprises a single coating material and is coated by one-layerapplication.
 12. The active compound formulation as claimed in claim 6,wherein the protective shell comprises a layer of natural or syntheticpolymer.
 13. The active compound formulation as claimed in claim 12,wherein the protective shell comprises a layer of a member selected fromthe group consisting of cellulose esters, ethers, acrylates,poly(meth)acrylates, polyamides, polyesters, copolymers ofacrylonitrile, styrene, ethylene, propylene, butadiene, esters ofmethacrylic acid, esters of acrylic acid, amides of methacrylic acid andamides of acrylic acid.
 14. The active compound formulation as claimedin claim 8, wherein the protective shell comprises cellulose ether. 15.The active compound formulation as claimed in claim 13, wherein theprotective shell comprises ethylcellulose.
 16. The active compoundformulation as claimed in claim 1, wherein the amount of the protectiveshell is 4-30 wt. %, based on total weight of formulation.
 17. Theactive compound formulation as claimed in claim 15, wherein the amountof the protective shell is 5-20 wt. %, based on total weight offormulation.
 18. The active compound formulation as claimed in claim 1,wherein the particle diameters are in the range of between 100 and 1000μm.
 19. The active compound formulation as claimed in claim 17, whereinthe particle diameters are in the range of between 200 and 800 μm. 20.The active compound formulation as claimed in claim 17, wherein theparticle diameter is between 400 and 600 μm.
 21. The active compoundformulation as claimed in claim 1, which has protection rates in the invitro release test after 6 h of 60-90%, and after 6-24 h of 10-60% after24 h.
 22. The active compound formulation as claimed in claim 20, whichhave protection rates in the in vitro release test after 6 h of 75-85%,and after 6-24 h of 35-50% after 24 h.
 23. A process for the preparationof a protected active compound by coating, which comprises coating theactive compound having a particle diameter of less than 1000 μm with aprotective shell of a coating material which is a natural or syntheticpolymer by fluidized bed coating or coacervation, and recovering acoated product with a particle diameter of a maximum of 1000 μm.
 24. Theprocess according to claim 23, wherein the polymer is a member selectedfrom the groups consisting of cellulose esters, ethers, acrylates,poly(meth)acrylates, polyamides, polyesters, copolymers ofacrylonitrile, styrene, ethylene, propylene, butadiene, esters ofmethacrylic acid, esters of acrylic acid, amides of methacrylic acid andamides of acrylic acid.
 25. The process as claimed in claim 23, whereinthe active compound is methionine in the form of crystalline orgranulate particles.
 26. The process as claimed in claim 23, wherein theactive compound is methionine in the form of platelet-shaped particlesor platelet-shaped crystals, round crystals, granules or spray granulesof a methionine salt which is suitable for feedstuffs use.
 27. Theprocess as claimed in claim 24, wherein the active compound ismethionine in form of crystalline or granulate particles.
 28. A processas claimed in claim 26, wherein methionine salt is Na, K, Ca, Mg, Znmethioninate in pure or mixed form.
 29. The process as claimed in claim26, wherein the protective shell comprises a single coating material andis applied by one-layer application.
 30. The process as claimed in claim26, wherein the protective shell comprises ethylcellulose.
 31. A processfor providing nutrition for ruminants comprising feeding the ruminatethe active compound formulation of claim
 1. 32. A feedstuff forruminants comprising ruminant feed and the active compound formulationof claim
 1. 33. Coated methionine containing particles protected by acoating, which comprises as the active compound a methionine or saltthereof, provided with a protective shell, having a particle diameter ofless than 1000 μm, and delayed release properties.
 34. The coatedmethionine particles as claimed in claim 33, wherein the active compoundis present in the form of crystals or granules.
 35. The coatedmethionine particles as claimed in claim 33, which is present inplatelet-shaped particles or crystals, or round crystals.
 36. The coatedmethionine particles as claimed in claim 34, wherein the active compoundis in the form of crystals, granules or spray granules of methioninesalts which are suitable for feedstuffs use.
 37. The coated methionineparticles as claimed in claim 36, wherein the salts are Na, K, Ca, Mg orZn salts.
 38. Coated methionine particles as claimed in claim 36,wherein the protective shell comprises a layer of cellulose esters,ethers, acrylates, poly(meth)acrylates, polyamides, polyesters orcopolymers of acrylonitrile, styrene, ethylene, propylene, butadiene, oresters and amides of methacrylic acid or acrylic acid.
 39. Coatedmethionine particles as claimed in claim 36, wherein the protectiveshell comprises a natural or synthetic polymer.
 40. Coated methionineparticles as claimed in claim 38, wherein the protective shell comprisesethylcellulose or cellulose.
 41. Coated methionine particles as claimedin claim 33, wherein the amount of the protective shell is 4-30 wt. %,based on the end product.
 42. Coated methionine particles as claimed inclaim 33, wherein the particle diameters are in the range of from 100 to1000 μm.
 43. Coated methionine particles as claimed in claim 42, whereinthe particle diameters are in the range of from 200 to 800 μm. 44.Coated methionine particles as claimed in claim 42, wherein the particlediameters are in the range of from 400 to 600 μm.
 45. Coated methionineparticles as claimed in claim 33, which has protection rates in the invitro release test after 6 h of 60-90%, and after 6-24 h of 10-60% after24 h.
 46. Coated methionine particles as claimed in claim 44, which hasprotection rates in the in vitro release test after 6 h of 75-85%, andafter 6-24 h of 35-50% after 24 h.